DESCRIPTION: (Applicant's Abstract) The goal of this proposal is to describe the cellular mechanisms of reorganization of two central cholinergic systems and their temporal relationships to recovery of spatial memory function following experimental traumatic brain injury in the rat. We will assess neurochemical and immunohistochemical cholinergic markers in the septal- hippocampal and nucleus basalis- neurocortical systems, as well as Morris water maze deficits, at specific time points following injury. Lastly, we will assess the effects of therapies that enhance cholinergic neurotransmission on specific neurochemical and immunohistologic markers, and on spatial memory performance. We have substantial published and preliminary data to suggest that chronic deficits in cholinergic neurotransmission deficits are attributable to reduction in the ability of cholinergic neurons to synthesize Ach, rather than a loss of cholinergic neurons. Reduced ach synthesis may be due to a reduction in choline transport, the rate-limiting step for the synthesis of ACh. Our general hypothesis is that severer traumatic brain injury (TBI) in rates produces long-term disturbances in central acetylcholine (ACh) neurotransmission which contribute to spatial memory deficits. To test this hypothesis, we have organized the proposed research into three sequential series of aims. the first Aim will determine the time course of three functionally distinct periods of recovery of spatial memory deficits following TBI. The first is an interval of "overt" spatial memory deficits that is characterized by performance deficits that are detectable by routine behavioral assessments. The second interval is characterized by deficits that are "covert" or undetectable in the absence of secondary pharmacological challenges does not differ between injured and non- injured animals. Aim 1 will be accomplished by measuring duration and magnitude of increased sensitivity to varying doses of an anticholinergic drug and an NMDA antagonist in the Morris water maze paradigm. The studies in Aim 1 are necessary to provide a rational basis for the selection of the post-traumatic time points use in Aim 2. The second Aim will systematically employ immunohistochemical, biochemical, and pharmacological techniques to determine if deficits of hippocampal and cortical cholinergic neurotransmission following TBI result from a low of cholinergic neurons or a loss of the cholinergic neuron's ability to function properly. We will evaluate loss of cholinergic neurons by measuring immunohistologic changes in ChAT and low-affinity NGF receptor- positive neurons in the medial septal and nucleus basalis regions. Changes in cholinergic terminal density will be assessed by autoradiographic binding of [3H]hemicholinium to the high-affinity choline uptake site. We will evaluate the ability of cholinergic neurons to function properly by measuring (1) levels of ChAT enzyme activity, (2) the capacity of in vitro tissue slices to synthesize and release acetylcholine, (3) in vivo ACh release using microdialysis, and (4) binding characteristics of muscarinic receptors and uptake sites. The last aim will determine whether chronic increases in cholinergic tone produced by administration of a cholinesterase inhibitor tetrahydrominoacridine (tacrine) will attenuate behavioral and neurochemical deficits in cholinergic neurotransmission in the hippocampus and cortex. Our long term goal is to develop new therapies to accelerate cognitive recovery following traumatic brain injury.